Mechanical activation of mammalian target of rapamycin pathway is required for cartilage development
Mechanical activation of mammalian target of rapamycin pathway is required for cartilage development
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DOI：
10.1096/fj.14-252783
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发表时间：
2014-10-01
期刊：
影响因子：
4.8
通讯作者：
Chen, Qian
中科院分区：
文献类型：
--
作者：
Guan, Yingjie;Yang, Xu;Chen, Qian
机械应力通过调节细胞信号和基因表达来调节发育。然而，介导机械转导的细胞质组分仍不清楚。在这项研究中，在鸡胚胎发育过程中消除肌肉收缩导致软骨生长板中哺乳动物雷帕霉素靶蛋白（mTOR）的活性降低。mTOR活性的抑制导致软骨细胞增殖、软骨组织生长和软骨形成基因的表达的显著抑制，所述软骨形成基因包括印度刺猬（Ihh），其是机械转导的关键介质。相反，在三维（3D）胶原支架中的胚胎鸡生长板软骨细胞的循环负荷（1 Hz，5%基质变形）诱导mTOR的持续激活。mTOR的机械活化发生在无血清培养基中，表明它不依赖于生长因子或营养素。用Rapa处理软骨细胞废除了细胞增殖和Ihh基因表达的机械活化。循环加载缺乏含SH 2的蛋白酪氨酸磷酸酶2（Shp 2）的软骨祖细胞进一步增强mTOR的机械活化、细胞增殖和软骨形成基因表达。该结果表明Shp 2是通过抑制mTOR活性的机械转导的拮抗剂。我们的数据表明，mTOR的机械激活是骨发育过程中细胞增殖、软骨形成和软骨生长所必需的，并且mTOR是细胞质中由Shp 2调节的重要机械转导组分。Guan，Y.，杨，X.，杨伟，沙博诺角陈角，澳-地机械激活哺乳动物雷帕霉素靶蛋白通路是软骨发育所必需的。
Mechanical stress regulates development by modulating cell signaling and gene expression. However, the cytoplasmic components mediating mechanotransduction remain unclear. In this study, elimination of muscle contraction during chicken embryonic development resulted in a reduction in the activity of mammalian target of rapamycin (mTOR) in the cartilaginous growth plate. Inhibition of mTOR activity led to significant inhibition of chondrocyte proliferation, cartilage tissue growth, and expression of chondrogenic genes, including Indian hedgehog (Ihh), a critical mediator of mechanotransduction. Conversely, cyclic loading (1 Hz, 5% matrix deformation) of embryonic chicken growth plate chondrocytes in 3-dimensional (3D) collagen scaffolding induced sustained activation of mTOR. Mechanical activation of mTOR occurred in serum-free medium, indicating that it is independent of growth factor or nutrients. Treatment of chondrocytes with Rapa abolished mechanical activation of cell proliferation and Ihh gene expression. Cyclic loading of chondroprogenitor cells deficient in SH2-containing protein tyrosine phosphatase 2 (Shp2) further enhanced mechanical activation of mTOR, cell proliferation, and chondrogenic gene expression. This result suggests that Shp2 is an antagonist of mechanotransduction through inhibition of mTOR activity. Our data demonstrate that mechanical activation of mTOR is necessary for cell proliferation, chondrogenesis, and cartilage growth during bone development, and that mTOR is an essential mechanotransduction component modulated by Shp2 in the cytoplasm.-Guan, Y., Yang, X., Yang, W., Charbonneau, C., Chen, Q. Mechanical activation of mammalian target of rapamycin pathway is required for cartilage development.